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Gynecologic Tumor Markers Tumor Marker Overview

Tumor Marker Overview

Tumor markers are soluble glycoproteins that are found in the blood, urine, or tissues of patients with certain types of cancer. They are typically produced by tumor cells, but in some cases they may be produced by the body in response to malignancy or to certain benign conditions. Tumor markers are not elevated in all cancer patients, particularly patients with early-stage cancer. The various tumor markers differ in their usefulness for screening, diagnosis, prognosis, assessing therapeutic response, and detecting recurrence.

Normalization of tumor marker values may indicate cure despite radiographic evidence of persistent disease. In this situation, residual tumor is frequently nonviable. Sometimes, tumor marker values may rise after effective treatment (due to cell lysis), but the increase may not portend treatment failure. A consistent increase in a tumor marker value, combined with lack of clinical improvement, may indicate treatment failure. Residual elevation after definitive treatment usually indicates persistent disease.

Many new tumor markers have been discovered since the development of monoclonal antibodies, and most tumor markers are now detected with them. No marker is completely specific. Therefore, diagnostic immunohistochemistry must be used in conjunction with morphologic and clinical findings.

Types of gynecologic tumor markers

Ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms are gynecologic malignancies for which tumor markers are in clinical use. The following are important gynecologic tumor markers:

Cancer antigen 125 (CA-125)

Beta human chorionic gonadotropin (beta-hCG)

Urinary gonadotropin fragment

Alpha-fetoprotein (AFP)



Carcinoembryonic antigen (CEA)

Squamous cell carcinoma (SCC) antigen

Müllerian inhibiting substance (MIS)

Topoisomerase II

Carbohydrate antigen 19-9

Cancer antigen 27-29

Human telomerase reverse transcriptase (hTERT)


Other potential gynecologic tumor markers include the following:

Lysophosphatidic acid

MIB1-determined tumor growth fraction

L1 (CAM)


Human epididymis protein 4 (HE4)


Vascular endothelial growth factor (VEGF)

Interleukin 8 (IL-8)

Macrophage colony-stimulating factor (M-CSF)

Insulinlike growth factor–binding protein-3

Tumor-associated trypsin inhibitor

Cyclin E


CA-15-3, CA-19-9

Clinical usefulness of tumor markers

The usefulness of a tumor marker is in its sensitivity and specificity, as well as its influence on patient management decisions. Because pathologic diagnosis of ovarian cancer is difficult without laparotomy, tumor markers such as CA-125, in addition to diagnostic imaging, are useful in preoperative evaluation for ovarian cancer.

No tumor markers with high sensitivity and high specificity for endometrial cancer are known at present, although CA-125 is often used in clinical practice. However, in a retrospective analysis (2008-2011) evaluating the utility of preoperative tumor markers in predicting prognostic parameters in women with pure endometrioid type endometrial cancer who underwent adjuvant therapy, investigators noted elevated levels of CA-125 was significantly able to predict for the following

Extrauterine disease

Tumors larger than 2 cm

Invasion of the lymphovascular space and of the deep myometrium

Involvement of the cervix and adnexa

Positive cytology

Lymph node metastasis

Requirement for adjuvant treatment

In addition, mean levels of CA-15-3 and CA-19-9 were significantly higher in women who required adjuvant therapy, and levels of CA-19-9 were also predictive of deep myometrial invasion, cervical involvement.
CEA and AFP levels were inadequately able to predict any of the evaluated poor prognostic parameters and requirements for adjuvant treatment.

SCC antigen is useful in the clinical management of advanced cervical cancer. Beta-hCG and alpha-fetoprotein have proved to be useful markers for ovarian germ cell tumors. In addition, beta-hCG serves as an ideal tumor marker for monitoring gestational trophoblastic disease and has set the standard with which other assays must be compared.

Studies aimed at improving the detection of epithelial ovarian cancers, especially at an early stage, have identified several new candidates for markers. These include lysophosphatidic acid (a lipid found in serum and ascitic fluid), mesothelin, HE4, osteopontin, VEGF, IL-8, M-CSF, and different kallikreins.

Among these potential markers, HE4 has sensitivity similar to CA-125 in detecting late-stage disease and greater specificity than CA-125 in detecting early ovarian cancer. Validation of HE4 as a diagnostic biomarker for early-stage ovarian cancer is ongoing. New approaches to facilitate identification of novel markers that may be altered early in disease include high-throughput techniques using microarray technology and proteomic screening.

To distinguish porocarcinoma from squamous cell carcinoma, cytokeratin 19 can be a helpful marker. A study by Mahalingam et al found diagnostic sensitivity and specificity to be improved using a selected panel of immunohistochemical stains that includes cytokeratin 7, cytokeratin 19, and nestin.

For more information, see Ovarian Cancer.

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